Abstract
Objectives: Inflammatory bowel disease (IBD) has been associated with restless leg syndrome (RLS). This study aims to explore the prevalence, clinical predictors, and severity of RLS in IBD patients compared to controls.
Methods: We conducted a case-control study between January and December of 2019 comparing IBD patients with controls. Assessment of RLS was performed using the previously validated diagnostic restless leg syndrome questionnaire (RLSQ). Logistic regression analyses were applied to investigate associations between patient demographics and clinical features and RLS diagnosis.
Results: A total of 218 IBD patients and 211 healthy controls were incorporated after excluding 6 patients with positional discomfort and 4 patients with habitual foot tapping. The mean age was 30.2±11.7 and 64% were females. The prevalence of RLS was 16/218 (7.34%) and 17/211 (8.06%) among cases and controls, respectively. Based on the RLSQ severity score, 6/16 (37.5%), 4/16 (25%) and 1/16 (6.3%) of the IBD patients with RLS had mild, moderate and severe RLS; respectively. The odds of IBD were lower among patients with confirmed RLS (OR=0.90, 95% CI=0.44-1.84, p = 0.78). In the logistic regression analysis, only vitamin B12 deficiency (OR=10.20, 95% CI=1.40-74.10, p = 0.022) was associated with RLS diagnosis among IBD patients.
Conclusion: No difference was found in the prevalence of RLS between IBD patients and non-IBD controls. Vitamin B12 deficiency was associated with RLS diagnosis among patients with IBD.
Inflammatory bowel disease (IBD) is a family of chronic inflammatory disorders that cause inflammation of the gastrointestinal tract. It comprises two main conditions: ulcerative colitis (UC) and Crohn’s disease (CD). Approximately 30% of IBD patients suffer from extra-intestinal manifestations (EIMs), which can involve the rheumatologic, musculo-cutaneous, and hepato-biliary systems.1,2 Anemia is a common manifestation of IBD that can be attributed to iron, folate (folic acid), or vitamin B12 deficiencies.3
Patients with IBD may develop neurological symptoms as part of the disease itself or through secondary complications, such as anemia. Perhaps one of its most distressing neurological manifestations is restless leg syndrome (RLS), which is a movement disorder characterized by an uncomfortable sensation in the legs which engenders restlessness temporarily relieved by movement. This discomfort takes place most commonly during night and when resting, and often disturbs sleep.4 Iron deficiency anemia (IDA) has been strongly associated with RLS.5,6 The RLS can be primary, i.e., idiopathic, or secondary, and is believed to be caused by both genetic and environmental factors.7 The most common secondary causes of RLS include iron deficiency and kidney disease; other causes include cardiovascular disease, arterial hypertension, diabetes, liver cirrhosis, migraine, Parkinson’s disease, and pregnancy.7-9 In a previous study conducted in Saudi Arabia, the prevalence of RLS among IBD patients was estimated to be 21.5%, compared to 9.7% in controls.10 Another study reported a 10% prevalence rate of RLS in North America and Europe, which is much higher than the prevalence rate reported by studies from Asian countries (0.6-1.8%).9 In contrast to many findings in Asian countries, the prevalence of RLS has been reported to increase with age in Europe, North America, and Saudi Arabia,10,11 and women have a higher prevalence of RLS compared to men.11,12 Moreover, it has been suggested that patients with RLS have poorer health and quality of life.11 This study describes the prevalence, clinical predictors, and severity of RLS in IBD patients compared with healthy controls.
Methods
We conducted a case-control study comparing healthy controls with IBD patients seen at the outpatient department of King Abdulaziz University Hospital (KAUH), Jeddah, Kingdom of Saudi Arabia between January and December of 2019. Ethical approval was obtained from the Research Committee at the Biomedical Ethics Unit at KAUH (Reference #147-19). Written consent was obtained for all participants. All patients diagnosed with UC or CD were identified and recruited with no age restrictions. Diagnosis of CD and UC was based on standard clinical criteria. Clinical, laboratory, endoscopic, radiologic, and histologic data were collected. Patients with symptoms consistent with habitual foot tapping or positional discomfort were excluded. Controls with a history of habitual foot tapping, positional discomfort neuroleptic-induced akathisia, peripheral neuropathy and radiculopathy, diabetes mellitus (DM), Parkinson’s disease, end stage renal failure, rheumatoid arthritis (RA), scleroderma, hyperparathyroidism, symptomatic peripheral neuropathy, migraine, attention defect, multiple sclerosis, pregnancy, organ failure, lung transplantation, pre-existing fibromyalgia, tremors, or bruxism were excluded.
Restless leg syndrome diagnosis and evaluation
Assessment of RLS was performed using the restless leg syndrome questionnaire (RLSQ),13,14 which is a self-rating questionnaire that comprises 3 parts: the first part explores administrative, demographic, past medical history of any chronic illness and medication history, smoking habits, physical examination (anthropometric measures), and laboratory results of vitamin D; the second part is composed of the RLS diagnostic criteria items 1-4 (Table 1); and the third part addresses each criterion through a set of closed questions, requiring “YES” or “NO” answers. All of the criteria must have been met for a diagnosis of RLS. Family history and assessment of the severity of the symptoms was estimated by the third part of the questionnaire, which comprised a severity rating scale and an inquiry about family history of RLS. This consisted of 10 questions, where each item had a set of five responses to choose from: 0=none, 1=mild, 2=moderate, 3=severe, 4=very severe. A total score could range between 0 and 40, which was subcategorized as follows: a score of 0 was none, a score of 1-10 was mild, a score of 11-20 was moderate, a score of 21-30 was severe, and a score of 31-40 was very severe.
The restless leg syndrome diagnostic criteria. shall we add
Selection of controls
Controls free of any GI symptoms that did not have a previous diagnosis of IBD were randomly selected and recruited from the outpatient clinics and from social media platforms.
Outcomes
The primary outcome of the study was to estimate the prevalence of RLS among IBD cases relative to controls. The secondary outcome was to identify predictors of RLS (and severe RLS) among patients with IBD.
Sample size calculation and statistical analysis
For sample size calculation, we hypothesized that the incidence of RLS detection (outcome) in patients with IBD (exposure) is twice as high as the baseline incidence rate of RLS in the general population (20% versus 10%). Assuming a type 1 error of 0.05 and 80% power to detect RLS, we estimated that 219 IBD patients and 219 healthy controls would be needed to detect an odds ratio (OR) of at least 2 (2-sided). This was calculated using OpenEpi, version 3 based on the reported prevalence rate in Saudi Arabia.15
Descriptive statics were used for quantitative variables, including means, standard deviations (SD), and minimum and maximum values or medians with inter quartile ranges (IQR), and summarized where appropriate. For qualitative variables we used frequencies measurement. McNemar’s test was incorporated to estimate the odds of IBD (exposure) vs. no IBD (no exposure) in RLS patients (cases) relative to healthy controls.
Logistic regression was applied to investigate associations between patient clinico-demographics features and RLS among patients with IBD; OR with 95% confidence intervals (CI) were reported. Linear regression analysis was utilized to identify predictors of RLSSS and regression coefficients (Coef.) with 95% CI were generated. A p-value of <0.05 was set as statistically significant. Stata/IC 12.1 for software for Mac (StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP.) was used for all analysis.
Results
Baseline characteristics
A total of 218 IBD patients and 211 healthy controls were included after excluding 6 patients with positional discomfort and 4 patients with habitual foot tapping. The mean age was 30.3±11.8 and 64.6% were females. Seventy-seven percent of the participants were non-smokers, and 91.8% did not have a family history of IBD (Table 2).
Baseline characteristics of the study cohort.
Study outcomes
The RLS was diagnosed in 16/218 (7.34%) and 17/211 (8.06%) of IBD cases and non-IBD controls, respectively; the prevalence ratio of prevalence ratio of 0.91 (95% CI=0.47-1.76, p = 0.78) was not statistically significant. Responses to the RLS screening questionnaire are outlined in Table 3.
Results of the RLS screening questionnaire for the study cohort.
The likelihood of having IBD in patients with confirmed RLS relative to those that did not have RLS is expressed by the (OR=0.90, 95% CI=0.44-1.84, p = 0.78), which is not statistically significant (Table 4). Based on the RLSQ severity score, 6/16 (37.5%), 4/16 (25%) and 1/16 (6.3%) of the IBD patients with RLS had mild, moderate and severe RLS, respectively (Table 5).
The study outcome comparing the odds ratio of IBD in patients with and without RLS.
Responses to the restless leg syndrome questionnaire comparing IBD patients and controls and a comparison of severity scores between the 2 cohorts.
Predictors of RLS and severe RLS among IBD Patients
In a logistic regression analysis, only Vitamin B12 deficiency (OR=10.2, 95% CI=1.40-74.10, p = 0.022) was associated with RLS diagnosis among patients with IBD (Table 6).
Predictors of restless leg syndrome and severe restless leg syndrome among IBD patients according to multiple logistic and linear regression analysis, respectively.
Linear regression analysis identified male gender to be negatively associated with RLS severity (Coef.= -2.73, 95% CI=-4.47 - -0.98, p = 0.002), and DM (Coef.=5.74, 95%=0.61 – 10.87, p = 0.029) and hypothyroidism (Coef.=5.92, 95% CI=0.86 – 10.99, p = 0.022) to be positively associated with more severe forms of RLS (Table 6).
Discussion
The RLS etiology is poorly understood, but a high prevalence of RLS has been linked with several diseases, such as kidney disease, cardiovascular disease, hypertension, obesity, respiratory disease, insomnia, mental illness7,8,16-18 arthritis, anemia, and DM.19-23 Moreover, literature that links RLS with IBD is often contradictory. Therefore, our study aimed to assess the prevalence of RLS in IBD patients in comparison with controls who did not have IBD. Our results suggest that RLS is less likely to occur in IBD patients relative to controls (OR=0.90, 95% CI=0.44-1.84, p = 0.78) with a prevalence ratio of 0.91 (95% CI=0.47-1.76, p = 0.78). By contrast, a number of other studies have suggested that RLS occurred more frequently in patients with IBD than the general population, with a reported prevalence rate of between 20% and 30%,2,9,10,22 although our prevalence rate was similar to that of one other study (8.8%).24
Many studies have assessed the severity of RLS and reported the presence of moderate to very severe distressing manifestations in 55.2% to 97.2% of patients,13,25-28 and very severe distressing manifestations in 2.3% to 5%.13,26,27,29 By contrast, our study results revealed that the majority of IBD patients with RLS had mild (37.5%) or moderate (25%) RLS symptoms. Furthermore, most studies have shown that the prevalence of RLS is more common in females than males;12,22,24-27,29 however, this inequality in gender is found mainly with respect to more severe manifestations.12 Also, some studies have reported that moderate to severe manifestations are more predominant among females than males.12,30 Results of our analysis are consistent with this finding as among our cohort of IBD patients, more severe forms of RLS were seen among females (-2.73, 95% CI=-4.47- -0.98, p = 0.002). Other predictors of severity included DM (Coef.=5.74, 95%=0.61–10.87, p = 0.029) and hypothyroidism (Coef.=5.92, 95% CI=0.86–10.99, p = 0.022).
Multiple previous studies have reported a significant association between RLS and older age,10,21,31 which is not supported by our results (OR=1.04, p = 0.09), although there was an observed non-significant statistical trend. Results from a study that evaluated RLS in a cohort of Greek patients with IBD described an increased prevalence of RLS observed before 79 years, and a decreased prevalence above this age.31 In a study of French adults, the prevalence of RLS appeared to increase with age up to 64 years, and then declined,26 and a Turkish study reported an increase in RLS prevalence with increasing age up to 67 years followed by a drop thereafter.21 In contrast, some other studies found no relationship between the prevalence of RLS and age.18,27
According to our analysis, having confirmed vitamin B12 deficiency is associated with RLS (OR=10.2, 95% CI=1.40-74.10, p = 0.022). This finding is supported by previous studies19,23,24 that have associated RLS with vitamin B12 and found that replacing vitamin B12 alleviated RLS symptoms.23 By contrast, Tasdemir et al21 have found no association between RLS and vitamin B12 deficiency. Previous studies have considered varicose veins and habitual foot tapping to be RLS mimickers, and excluded them from the diagnosis of RLS.19 We therefore elected to exclude patients with symptoms consistent with habitual foot tapping or positional discomfort, both of which could be confused with RLS. Varicose veins has been previously associated with RLS but our study results did not support this notion as the association between RLS and varicose veins based on multiple regression analysis appeared to be non-significant statistically (OR=5.1, 95% CI=0.68-36.92, p = 0.11).20,32-34 Moreover, 2 of these studies note that an improvement in RLS symptoms often occurs after superficial venous insufficiency is treated surgically.33,34 According to the RLSSS and based on our linear regression analysis, other predictors of severe RLS include male gender (Coef.=-2.73, 95% CI= -4.47- -0.98, p = 0.002), DM (Coef.=5.74, 95% = 0.61 – 10.87, p = 0.029) and hypothyroidism (Coef.=5.92, 95% CI=0.86 – 10.99, p = 0.022).
We acknowledge that our study is limited by its cross-sectional design and the use of a self-reported questionnaire to assess for RLS symptoms. Another limitation is the absence of data concerning hemoglobin levels for statistical adjustment. This was decided owing to the difficulty anticipated with the acquisition of such test samples from a large population of controls.
In conclusions, in this Saudi Arabian cohort, patients with IBD had no increase in the prevalence of RLS when compared to non-IBD controls. Vitamin B12 deficiency was associated with RLS diagnosis. Female gender, DM and hypothyroidism were associated with more severe forms of RLS.
Statistics
Excerpts from the Uniform Requirements for Manuscripts Submitted to Biomedical Journals updated November 2003.
Available from www.icmje.org
Describe statistical methods with enough detail to enable a knowledgeable reader with access to the original data to verify the reported results. When possible, quantify findings and present them with appropriate indicators of measurement error or uncertainty (such as confidence intervals). Avoid relying solely on statistical hypothesis testing, such as the use of P values, which fails to convey important information about effect size. References for the design of the study and statistical methods should be to standard works when possible (with pages stated). Define statistical terms, abbreviations, and most symbols. Specify the computer software used.
Acknowledgment
We would like to thank Marah A. Alarawi, Daniah S. Allbdi, Wejdan A. Alshehri, Maram M. Alzahrani, and Sara M. Mannan for their kind help in the collection of data, and Dr. Trevor Rawbone, Cardiff, UK for kindly reviewing the manuscript.
Footnotes
Disclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company.
- Received February 21, 2020.
- Accepted May 4, 2020.
- Copyright: © Neurosciences
Neurosciences is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.
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